Drug Discovery and Development: The Drug Discovery Process

In the drug discovery process, the main focus is to help the patient overcome a disease and improve their quality of life. It is designed to ensure that innovative new medicines are effective, safe and available for patients in the shortest possible time. The drug discovery process begins with choosing a disease. The drug discovery process is made up of different stages and is the first part of a chain that takes a discovered drug through to distribution (Strovel et al., 2012). There are two distinct phases to discovering and commercialising medicine. The first phase is the discovery phase. This involves pre-discovery which is when lots of information is gathered about a certain disease to be able to understand the nature of the disease and therefore how to treat it (Strovel et al., 2012). The discovery programs are usually focused on disease targets such as proteins in the patient’s body which are associated with a disease or proteins in microorganisms causing a disease. Additionally it  produces a variety of different molecules; however, this can be argued as unsuccessful due to many factors including copyright, safety and activity (C. Mohs et al., 2017).

Pharmaceutical companies tend to avoid diseases that affect a minority of people as it is expensive to research and develop new drugs (Field et al., 2010). Diseases that affect only the third world countries will often be avoided due to their low economic status and pharmaceutical companies concentrate on developing drugs for diseases that are prevalent in developed countries and aim to develop better compounds with better properties than existing drugs (Leisinger et al., 2012). A majority of the research is put into diseases such as cancer, depression, diabetes, obesity and cardiovascular diseases rather than tropical diseases unless the tropical diseases start to have an impact on richer countries (Boutayeb et al., 2005). The orphan drug act was passed in 1983 which encourages pharmaceutical companies to discover drugs for diseases affecting less than 200,000 people in the US. This is beneficial for the company as they will be able to market it without competition for 7 years (Fagnan et al., 2014)

Pre-Clinical Research

Once a disease has been chosen it is then suitable to choose a drug target. This is a target molecule that a drug needs to find and act on. It is often a protein molecule such as an enzyme. It is essential for the disease being treated to be understood on a molecular level using genomics, bioinformatics and proteomics (Hughes et al., 2011). Researchers also need to look for proteins or mRNA that have been expressed/not expressed in a disease using comparative gene expression assays or comparative proteomic profiles. They need to identify genes or proteins essential for the infectious agents or gene/protein modifications associated with the disease (Hughes et al., 2011). Regulatory pathways required for the disease process need to be found. Experimental techniques such as NMR, EM, Protein DataBank and SwissProt are used to predict protein structures. Prediction of protein structures is important to fill any gaps between known sequences and structures and for rational drug design (Schmidt et al., 2014).

To elaborate on experimental techniques, X-ray crystallography and nuclear magnetic resonance (NMR) are used to solve the structure of 3D proteins. X-ray crystallography can be used on a protein of any size and was the first to be used to identify the 3D structure of a protein. When an electron is hit by x-rays the electron starts vibrating and secondary beams are scattered in all directions. The scattering is secondary radiation which will interact and cause interference. The scattering of a molecule is dependent on its structure therefore if we know the phases of a scattered molecule, we can calculate the structure.

After the drug target has been chosen, it is important to identify a bioassay. A bioassay is a test used to determine biological activity. Choosing the appropriate bioassay is crucial to the success of drug research. The test should be quick and relevant as there are many compounds needed to be analysed. The test is done in vitro first, which are cheaper, easier and less controversial than in vivo tests. In vivo tests need to check drug interactions and pharmacokinetics. In vitro tests involve isolated specific tissues and cells or enzymes and are tested on in a laboratory. Antibacterial drugs are tested in vitro. In vivo tests are tested on animals in clinical conditions to observe symptoms. The animal is treated with the drug to see whether the symptoms are alleviated. Most of the time the validity of the testing procedure is clear and easy but other cases display a more difficult test e.g. antipsychotic drugs. This is because anti-psychotic drugs have a variety of common side effects from weight gain and sexual dysfunction to postural hypertension and type II diabetes. (Hughes et al., 2011). High throughput screening (HTS) involves the in vitro testing to be automated so that a large number of tests can be carried out in a short period of time. The tests should show an easily measurable effect such as cell growth or enzyme reaction. Additionally, these tests increase the likelihood in supporting drug target intervention for a group of disease states (Szymański et al., 2012).

Once the bioassay has been identified, the ‘lead compound’ needs to be determined. The lead compound is a structure that has some activity against the chosen target but not yet good enough to be the drug itself. This can be done by identifying structure-activity-relationships (SAR’s) (Lakshmana Prabu et al., 2014). The pharmacophore contains the structural features directly responsible for activity and the lead compound can be identified when the pharmacophore is identified. Knowing this can optimise the structure and improve interactions with the target. The pharmacokinetics and pharmacodynamics of the drug should be determined. These molecules need to carry pharmacokinetic properties in order for the drug to be synthesised and promote the binding of the drug to the target (Buynak, 2008). In 1991, the use of PK properties has advantageously reduced the number of molecules entering the stage of clinical development and has strategically countered against drug development failures, from 40% in 1991 to 10% in 2000 (C. Mohs et al., 2017)

Clinical Research

The development phase occurs after the potential drug and mechanisms (lead compound) have been identified (National Academic Press, 2014). This includes pre-clinical testing to determine whether the drug is appropriate to test on humans. Once the drug has proved safe enough for human testing, a CTX (clinical trial exceptions) application needs to be put through so that the 3 phases of clinical trials can begin. Phase 1 clinical trial is when a small group of healthy human volunteers test the drug. Phase 2 clinical trial is when the drug is tested on a small group of patients and phase 3 is when a large group of patients with the disease are tested to show efficacy and safety.  Figures shown by the FDA have estimated that 70% of drugs have passed through phase 1, a third through phase 2 and 25-30% through phase 3 (Step 3: Clinical Research, 2018). The next step is to patent the drug. The drug metabolism and toxicity need to carry on being tested. Once this is done the manufacturing process can be designed along with carrying out clinical trials then marketing the drug (Hughes et al., 2011).

Drug Review, Approval and Monitoring

One the drug has proved successful and safe for many of the patients, marketing and manufacturing can occur on a full-scale. The drug still needs to undergo constant monitoring whilst in use (phase 4 trials) (C. Mohs et al., 2017). Although the process of manufacturing is arduous and expensive, it is manufactured to the highest quality of purification and stabilisation which is met by regulatory officials to ensure it meets satisfactory needs. Once it has been accepted, medicines are approved by the medical community and given to patients in prescribed measures. The cost of the drug that gains marketing approval is estimated to be $2.5 million (C. Mohs et al., 2017). However, side effects are still monitored whilst the drug is available to use in clinical trials. For example, one commonly known drug that went through the process of manufacturing and approval but later discovered to have severe side effects was Thalidomide. Thalidomide was used to treat morning sickness in pregnant women but later realised it resulted in severe birth defects such as shortened limbs. Today, it is used to treat many forms of cancer including blood and bone marrow cancers such as leukaemia and myelofibrosis. (Fintel et al., 2009)

The drug discovery and development process have manifested over the years into becoming the key to delivering new medicines as a worldwide tool.  It has evolved into advancing new molecular tools to approach different therapies. Additionally, it has a substantial offering to marketing and gives an investment that is both high-risk and expensive towards research for new unknown discoveries of medicine. Despite this, its future holds great potential for therapeutic intervention.

References

• Boutayeb, A., Boutayeb, S., 2005. The burden of non communicable diseases in developing countries. International Journal for Equity in Health, Volume 4(1), pp.2. (Accessed: 8^th October 2018) Accessed online at: https://equityhealthj.biomedcentral.com/articles/10.1186/1475-9276-4-2
• Buynak, J., (2008) ‘Drug Discovery and Development’[PowerPoint presentation]. (Accessed: 5^th October 2018) Accessed online at: https://faculty.smu.edu/jbuynak/drugdiscoverydevelopment2011.ppt
• C. Mohs, R. and H. Greig, N., 2017. Drug discovery and development: Role of basic biological research.  Alzheimer’s & Dementia: Translational Research & Clinical Interventions, Volume 3(4), pp.651-657. (Accessed: 4^th October 2018) Accessed online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725284/
• Fagnan, David E., Gromatzky, Austin A., Stein, Roger M., Fernandez, Jose-Maria., Lo, Andrew W., 2014. Drug discovery today. Financing drug discovery for orphan diseases, Volume 19(5), pp.533-8. (Accessed: 7^th October 2018) Accessed online at: https://www.ncbi.nlm.nih.gov/pubmed/24269746
• Field, MJ., 2010. Institute of Medicine (US) Committee on Accelerating Rare Diseases Research and Orphan Product Development, Volume 6.  (Accessed: 5^th October 2018) Accessed online at: https://www.ncbi.nlm.nih.gov/pubmed/21796826

         Fintel, Bara., T.Samaras, Athena., Carias, Edson., 2009. The Thalidomide Tragedy: Lessons for Drug Safety and Regulation. (Accessed: 8^th October) Accessed online at: https://helix.northwestern.edu/article/thalidomide-tragedy-lessons-drug-safety-and-regulation

• Hughes, J., Rees, S., Kalindjian, S., Philpott K., 2011. Principles of early drug discovery. British Journal of Pharmacology, Volume 162(6), pp.1239-1249. (Accessed: 5^th October) Accessed online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058157/
• Lakshmana Prabu, S., Thirumurugan, R., Suriyaprakash, T.N.K., 2014, The Role of the Drug Discovery, Clinical, and Regulatory Affairs Teams in Turning a Potent Agent into a Registered Product. (Accessed: 9^th October 2018) Accessed online at: https://www.researchgate.net/publication/285671282_The_Role_of_the_Drug_Discovery_Clinical_and_Regulatory_Affairs_Teams_in_Turning_a_Potent_Agent_into_a_Registered_Product
• Leisinger, KM., Garabedian L.F., Wagner AK., 2012. Improving Access to Medicines in Low and Middle Income Countries: Corporate Responsibilities in Context. Southern Med Review, Volume 5(2), pp.3-8. (Accessed: 5^th October 2018) Accessed online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606933/
• National Academies Press (US), 2014. Forum on Neuroscience and Nervous System Disorders; Board on Health Sciences Policy; Institute of Medicine. Improving and Accelerating Therapeutic Development for Nervous System Disorders: Workshop Summary, pp.2. (Accessed: 10^th October 2018) Accessed online at: https://www.ncbi.nlm.nih.gov/pubmed/24354031
• Schmidt, T., Bergner, A., Schwede, T., 2014. Modelling three-dimensional protein structures for applications in drug design. Drug discovery today, Volume 19(7), pp.890-897. (Accessed: 9^th October) Accessed online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112578/
• Step 3: Clinical Research (2018), (Accessed: 8^th October 2018) Accessed online at: https://www.fda.gov/forpatients/approvals/drugs/ucm405622.htm
• Strovel, J., Sittampalam, S., Coussens, NP., et al., 2012. Early Drug Discovery and Development Guidelines: For Academic Researchers, Collaborators, and Start-up Companies, pp.8-10. (Accessed: 11^th October 2018) Accessed online at: https://www.ncbi.nlm.nih.gov/books/NBK92015/
• Szymański P., Markowicz M., Mikiciuk-Olasik E., 2012 Adaptation of High-Throughput Screening in Drug Discovery—Toxicological Screening Tests. International Journal of Molecular Sciences, Volume 13(1), pp.427-452. (Accessed: 12^th October 2018) Accessed online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269696/